The present invention relates generally to methods and apparatus for treating or controlling medical, psychiatric or neurological disorders by application of modulating electrical signals to a selected nerve or nerve bundle of the patient, and more particularly to techniques for treating patients with neuropsychiatric disorders by application of such signals to the vagus nerve or other suitable cranial nerve, using an implantable neurostimulator. Specifically, the invention is directed toward treating the symptoms of neuropsychiatric disorders such as schizophrenia, depression, and borderline personality disorder, by selective modulation of vagus nerve activity.
Although schizophrenia was initially thought to have only psychological origins, more recent psychobiology and psychopharmacology findings have indicated that the illness is primarily organic in nature. Electrophysiologic studies of patients with schizophrenia have supported an organic etiology. Although not entirely consistent, electroencephalogram (EEG) studies have tended to reveal abnormalities in these patients. Also, some parallels have been found between schizophrenia and epilepsy.
Developments in psychobiology and psychopharmacology have also provided considerable evidence that major depressive disorder and bipolar depression are biological rather than psychological diseases. The conclusion that depression has a biological basis is also supported by numerous electrophysiological and endocrine studies. Deficiency of brain neurotransmitters has been associated with depression. In particular, abnormally low concentrations of the neurotransmitter serotonin and its metabolites and norepinephrine have been found in depressed patients. Several serotonin uptake inhibitors, which increase the amount of serotonin at the synapse have been shown to be effective antidepressants. Iincreased activity of the vagus nerve has been postulated to be associated with release of increased amounts of serotonin and norepinephrine in the brain.
Borderline personality disorder is a poorly understood, but recognized psychiatric disorder which seems to have some overlap of schizophrenia and depression. Patients tend to be poorly functional without florid psychosis or overt depression. Lahmeyer et al. reported, in J. Clin. Psych. (1989) 50(6):217-225, that sleep architecture in patients with borderline personality disorder is disturbed in that REM latency is decreased and REM density is increased. This was found to be particularly true if patients suffered coexisting depression, a history of affective illness or a family history of psychopathology. Sleep abnormalities were reported to appear similar to those seen in affective disorders.
It is an object of the present invention to apply the techniques of selective modulation of vagus nerve electrical activity, using a neurostimulator device which may be implantable, or used external to the body with only a small portion of the circuitry implanted or with only the nerve electrode(s) and associated lead(s) implanted percutaneously in the body, to the treatment of neuropsychiatric disorders including schizophrenia, depression, and borderline personality disorder, as well as other neuropsychiatric disorders as defined in the Diagnostic and Statistical Manual of Mental Disorders.
In U.S. Pat. No. 5,299,569 (sometimes referred to herein as xe2x80x9cthe ""569 patentxe2x80x9d), assigned to the same assignee as the present application, Wernicke et al disclosed methods and devices for treating and controlling certain neuropsychiatric disorders by selective stimulation of the vagus nerve. A neurostimulator which is preferably but not necessarily implantable selectively applies the therapy to treat the specific neuropsychiatric disorder such as schizophrenia, depression, borderline personality disorder, or other related disorder. The therapy is delivered in a manner to stimulate or modulate the vagal activity of the patient in a predetermined manner to treat and relieve the symptoms of the disorder, although it may not be effective in alleviating the underlying root cause of the disorder. The neurostimulator is programmed by the attending physician to generate a pulsed electrical signal that provides the desired therapeutic modality for treatment.
In the ""569 patent, the applicants reported their conclusion that vagal stimulation can be effective for treating schizophrenia, for example. One observation toward that conclusion is that fast desynchronous (beta) activity and paroxysmal (synchronous) activity of the EEG have both been reported in studies of this disorder. At some stimulation parameters, vagal stimulation will synchronize the EEG, with a resultant beneficial effect on treatment of the disorder where increased beta wave activity is present. A second observation is the apparent relationship between schizophrenia and temporal lobe epilepsy. The temporal lobes are part of the limbic system, which they postulated is malfunctioning in patients with schizophrenia. Vagal stimulation can suppress temporal (complex partial) seizures, which are generated in the limbic system. The structures of this system are interconnected, and the beneficial effect of vagal stimulation seen in the temporal lobes may be transmitted to other brain structures, leading to a similar effect on schizophrenia. In this case, the abnormality being treated is a synchronous paroxysmal (epileptiform) discharge, and the therapy is designed to desynchronize the EEG.
In the treatment, different signal parameters and threshold curves are used to activate the various fibers of the patient""s vagus nerve for selective modulation thereof by appropriately setting pulse width and amplitude of the electrical signal to be delivered by the neurostimulator to the patient""s vagus nerve. It was recommended that to increase desynchronous activity of the EEG for treatment of a neuropsychiatric disorder, it would be prudent to use a short pulse train for the stimulus because the fibers could become refractory to the stimulation within a relatively short time interval. Then, after a suitable recovery period, another short pulse train may be applied to achieve further treatment. The precise pattern to be used, including the length of the time intervals on and off, depends upon and is adjusted to the individual patient and the particular disorder being treated.
The basic stimulation strategy called for modulating the activity of a number of brain structures, including the limbic system, the reticular formation, and the hippocampus through selective stimulation of the vagus nerve, which projects directly or indirectly to these brain structures. The strategy may be implemented by circadian programming to automatically activate the stimulus generator to continuously, periodically or intermittently generate an electrical signal appropriate for application to the patient""s vagus nerve to modulate its activity and that of these brain structures. In another aspect, the treatment is carried out by applying the selectively modulating electrical signals to the patient""s vagus nerve in response to the occurrence of one or more predetermined detectable events.
In the case of depression, vagal stimulation may be used to alter sleep state architecture as a modality that may produce a beneficial antidepressant effect. Certain stimulation parameters for the vagus nerve may produce synchronization of brain activity which leads to the biochemical changes required to relieve depression, without causing seizures. It is also noted in the ""569 patent that vagal stimulation may be effective in the treatment of borderline personality disorder, at least because of the abnormalities in sleep architecture attendant with such disorders and the capability of vagal stimulation to alter sleep states. Recently, left cervical vagus nerve stimulation has been shown to have antidepressant effects in the treatment of patients with major depression and bipolar disorder (Rush et al, Biological Psychiatry, February, 2000).
Methods and apparatus for treating and controlling neuropsychiatric disorders according to the ""569 patent involves applying electrical stimuli to the patient""s vagus nerve or other appropriate cranial nerve, which may activate a specific group of fibers from among all of the fiber groups of the selected nerve(s), and selectively synchronize or desynchronize the patient""s EEG and/or vary REM activity according to the specific nature of the disorder, and/or alter brain serotonin concentrations. Also, it was contemplated that the methods of treating and controlling neuropsychiatric disorders could be implemented by sensing a symptom of the disorder or the occurrence of a predetermined detectable event and thereafter automatically or manually effecting modulation of vagal activity through the application of preselected stimuli to the patient""s vagus nerve to suppress the disorder. For example, by means of implanted surface or depth electrodes specific characteristics of the patient""s EEG may be sensed for triggering the therapy. Alternatively, eye movement sensing electrodes may be implanted at or near the outer periphery of each eye socket to sense muscle movement or actual eye movement, and electrically connected via electrical leads to a sense signal analysis circuit of neurostimulator for rapid eye movement (REM) detection in a pattern indicative of the disorder to be treated. But since these sensing techniques involve complex and delicate electrode/lead implantation procedures, and in some instances a need for spectral analysis and/or programmable spectral or pattern recognition, it was preferred that the treatment be applied continuously, periodically or intermittently or in accordance with the patient""s circadian rhythm. In the preferred implementation of the ""569 patent, the electrode assembly is surgically implanted on the vagus nerve in a cervical location, in the patient""s neck. The nerve electrodes may be wrapped about the vagus nerve, and the assembly secured to the nerve by a spiral anchoring tether.
It is a principal aim of the present invention to provide a new technique for treating neuropsychiatric disorders using stimulation of a suitable cranial nerve, especially the vagus nerve.
According to the present invention, a method of treating patients suffering from neuropsychiatric disorder, such as but not limited to schizophrenia, depression, or borderline personality disorder, comprises unilateral or bilateral stimulation of the left and right vagi in the immediate vicinity of the patient""s diaphragm. Preferably, the treatment is administered at either a supra-diaphragmatic position (i.e., above the diaphragm) or sub-diaphragmatic position (i.e., below the diaphragm) in the ventral cavity. The stimulating electrical signal is preferably applied to the vagus two to three inches above or below the diaphragm, and may be applied either synchronously or asynchronously to both the right and left branches, preferably in the form of a series of pulses applied intermittently to both branches according to a predetermined on/off duty cycle. The intermittent application is preferably chronic, rather than acute. However, continuous application or acute application by bilateral stimulation of the right and left vagi or unilateral stimulation of either branch of the nerve is also contemplated.
Automatic delivery of bilateral intermittent stimulation is preferred, but alternatively in the case of certain neuropsychiatric disorders application of the stimulating electrical signal to the right and left vagi may be controlled by an external commencement signal produced by the patient""s placement of an external magnet or use of other appropriate device or signaling mechanism in proximity to the location of the implanted device.
Preferably, the same stimulating electrical signal is applied to both the right and left vagi, but as an alternative, a stimulating electrical signal might be applied to the right vagus which is different from the stimulating electrical signal applied to the left vagus. And although two separate nerve stimulator generators may be implanted for stimulating the left and right vagi, respectively, as an alternative a single nerve stimulator generator may be implanted for bilateral stimulation if the same signal is to be applied to both the left and right branches of the vagus nerve, whether delivered synchronously or asynchronously to the vagi.
Preferably, the current magnitude of the stimulating signal is programmed to be less than about 6 mA, to be below the retching level of the patient as determined by the implanting physician at the time the implant procedure is performed. This is desirable to avoid patient nausea during periods of vagus nerve stimulation. Preferably, the pulse width is set to a value not exceeding about 500 microseconds (xcexcs), the pulse repetition frequency is set at about 20-30 Hertz (Hz), the VNS regimen follows alternating periods of stimulation and no stimulation, with the second period about 1.8 to 6 times the length of the first period in the alternating sequence (i.e., the on/off duty cycle is 1:1.8 to 1:6).
Alternative techniques include indirect stimulation of the vagus, either bilaterally or unilaterally, at a location near one or both branches of the nerve or elsewhere, which has the effect of stimulating the vagus nerve as well. This may be accomplished through afferents or efferents, for example. It is also contemplated that direct or indirect unilateral or bilateral stimulation, applied in the vicinity of the patient""s diaphragm, of one or more of the other cranial nerves of suitable sensory, motor or mixed fiber types may be effective in treating neuropsychiatric disorder, as an alternative to vagus nerve stimulation.
Some differences may be observed from stimulator to stimulator in magnitude of current in the pulses of the stimulation signal, and may be attributable to things such as patient impedance, variation of the vagus nerve from right to left or between patients, and variation in contact between the vagus and the electrode implanted thereon from implant to implant.